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11.发明授权Medical devices incorporating deuterated rapamycin for controlled delivery thereof 失效结合氘化雷帕霉素的医疗装置用于其控制递送公开(公告)号：US06884429B2
公开(公告)日：2005-04-26
申请号：US10301504
申请日：2002-11-20
IPC分类号： A61L29/16 , A61L31/16 , C07D498/18 , A61M25/00 , A61F2/00
CPC分类号： C07D498/18 , A61L29/16 , A61L31/16 , A61L2300/416 , A61L2300/602
摘要： Deuterated rapamycin can be controllably introduced target locations within the patient's body by using an implantable medical device having a structure incorporated with a therapeutic agent comprising a deuterated rapamycin. Representative deuterated rapamycins include epi-7-deuteromthyl rapamycin, 7,43-d6 rapamycin, 7-deuteromethyl rapamycin and 31,42-d2-rapamycin and isomers thereof, and mixtures thereof. The deuterated rapamycin can also be glycosylated.
摘要翻译： 氘化雷帕霉素可以通过使用具有结合有包含氘化雷帕霉素的治疗剂的结构的可植入医疗装置来可控地引入患者体内的靶位置。 代表性的氘代雷帕霉素包括表7-降血磷酸雷帕霉素，7,43-d6N雷帕霉素，7-氘代甲基雷帕霉素和31,42-d2-雷帕霉素及其异构体， 及其混合物。 氘代雷帕霉素也可以糖基化。
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12.发明授权公开(公告)号：US06713266B1
公开(公告)日：2004-03-30
申请号：US09650684
申请日：2000-08-30
IPC分类号： G01N3353
CPC分类号： G01N33/9493 , A61K39/00 , C07K7/64 , C07K16/14
摘要： This invention relates to the production of polyclonal and monoclonal antibodies to specific regions of cyclosporine (CSA) and/or CSA metabolites/derivatives. The reactivity of these polyclonal and monoclonal antibodies make them particularly useful for immunoassays for therapeutic drug monitoring (TDM). These immunoassays or TDM kits may include polyclonal or monoclonal antibodies to specific sites of CSA and/or CSA metabolites. These kits may also include various combinations of polyclonal antibodies, polyclonal and monoclonal antibodies or a panel of monoclonal antibodies. Cyclosporine or CSA metabolite conjugate immunogens are prepared for the immunization of a host animal to produce antibodies directed against specific regions of the CSA or CSA metabolite molecule. By determining the specific binding region of a particular antibody, immunoassays which are capable of distinguishing between the parent molecule, active metabolites, inactive metabolites and other structurally similar immunosuppressant compounds are developed. The use of divinyl sulfone (DVS) as the linker arm molecule for forming cyclosporine and cyclosporine metabolite protein conjugate immunogens is described.
摘要翻译： 本发明涉及针对环孢菌素（CSA）和/或CSA代谢物/衍生物的特定区域的多克隆和单克隆抗体的产生。 这些多克隆抗体和单克隆抗体的反应性使其在治疗药物监测（TDM）的免疫测定中特别有用。 这些免疫测定或TDM试剂盒可以包括针对CSA和/或CSA代谢物的特定位点的多克隆或单克隆抗体。 这些试剂盒还可以包括多克隆抗体，多克隆和单克隆抗体或一组单克隆抗体的各种组合。 制备环孢菌素或CSA代谢物缀合物免疫原用于免疫宿主动物以产生针对CSA或CSA代谢物分子的特定区域的抗体。 通过确定特定抗体的特异性结合区域，开发了能够区分亲本分子，活性代谢物，无活性代谢物和其它结构相似的免疫抑制剂化合物的免疫测定。 描述了使用二乙烯基砜（DVS）作为形成环孢菌素和环孢菌素代谢物蛋白质结合物免疫原的连接臂分子。
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公开(公告)号：US06709873B1
公开(公告)日：2004-03-23
申请号：US09638900
申请日：2000-08-15
IPC分类号： G01N3353
CPC分类号： C07K16/14
摘要： This invention relates to the production of polyclonal and monoclonal antibodies to specific sites of rapamycin (Sirolimus). The reactivity of these poly and monoclonal antibodies make them particularly useful for immunoassays for therapeutic drug monitoring (TDM). These immunoassays or TDM kits may include polyclonal or monoclonal antibodies to specific sites of rapamycin. These kits may also include various combinations of polyclonal antibodies, polyclonal and monoclonal antibodies or a panel of monoclonal antibodies. Rapamycin conjugate immunogens are prepared for the immunization of a host animal to produce antibodies directed against specific regions of the rapamycin molecule. By determining the specific binding region of particular antibody, immunoassays which are capable of distinguishing between the parent molecule, active metabolites, inactive metabolites and other structurally similar immunosuppressant compounds are developed. The use of divinyl sulfone (DVS) as the linker arm molecule for forming rapamycin-protein conjugate immunogens is described. DVS-linked rapamycin-protein conjugates were found to elicit antibodies with greater specificity to the rapamycin molecule than succinate linked conjugates.
摘要翻译： 本发明涉及针对雷帕霉素（西罗莫司）特定部位的多克隆和单克隆抗体的产生。 这些多抗和单克隆抗体的反应性使其对治疗药物监测（TDM）的免疫测定特别有用。 这些免疫测定或TDM试剂盒可以包括针对雷帕霉素的特定位点的多克隆或单克隆抗体。 这些试剂盒还可以包括多克隆抗体，多克隆和单克隆抗体或一组单克隆抗体的各种组合。 制备雷帕霉素结合物免疫原用于免疫宿主动物以产生针对雷帕霉素分子的特定区域的抗体。 通过确定特定抗体的特异性结合区域，开发了能够区分亲本分子，活性代谢物，无活性代谢物和其他结构类似的免疫抑制剂化合物的免疫测定。 描述了使用二乙烯基砜（DVS）作为形成雷帕霉素 - 蛋白质结合物免疫原的连接臂分子。 发现DVS连接的雷帕霉素 - 蛋白质缀合物比琥珀酸酯连接的缀合物引发对雷帕霉素分子具有更高特异性的抗体。
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公开(公告)号：US07538189B2
公开(公告)日：2009-05-26
申请号：US11245775
申请日：2005-10-06
IPC分类号： A61K38/13
CPC分类号： C07K7/645 , A61K38/00 , C07B59/008 , C07K1/13 , C07K7/64 , Y10S530/806 , Y10S530/807
摘要： Cyclosporine derivatives are disclosed which possess enhanced efficacy and reduced toxicity over naturally occurring and other presently known cyclosporins and cyclosporine derivatives. The cyclosporine derivatives of the present invention are produced by chemical and isotopic substitution of the cyclosporine A (CsA) molecule by: (1) Chemical substitution and optionally deuterium substitution of amino acid 1; and (2) deuterium substitution at key sites of metabolism of the cyclosporine A molecule such as amino acids 1, 4, 9. Also disclosed are methods of producing the cyclosporine derivatives and method of producing immunosuppression with reduced toxicity with the disclosed cyclosporine derivatives.
摘要翻译： 公开了与天然存在的和其他目前已知的环孢菌素和环孢菌素衍生物相比具有增强的功效和降低的毒性的环孢菌素衍生物。 本发明的环孢菌素衍生物通过以下方式通过环孢菌素A（CsA）分子的化学和同位素取代产生：（1）氨基酸1的化学取代和任选的氘取代; 和（2）在环孢菌素A分子的代谢关键位置的氘代替，例如氨基酸1,4,9。还公开了产生环孢菌素衍生物的方法和与所公开的环孢菌素衍生物一起产生具有降低的毒性的免疫抑制的方法。
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15.发明授权公开(公告)号：US07332472B2
公开(公告)日：2008-02-19
申请号：US11118830
申请日：2005-04-28
IPC分类号： A61K38/13
CPC分类号： C07K7/645 , A61K9/0095 , A61K9/1075 , A61K9/4858 , A61K38/00 , A61K38/13 , B82Y5/00 , C07K7/64 , Y10S530/806
摘要： The invention is directed to isomeric mixtures of cyclosporine analogues that are structurally similar to cyclosporine A. The mixtures possess enhanced efficacy and reduced toxicity over the individual isomers and over naturally occurring and other presently known cyclosporines and cyclosporine derivatives. Embodiments of the present invention are directed toward cis and trans-isomers of cyclosporin A analogs referred to as ISATX247, and derivatives thereof. Mixtures of ISATX247 isomers exhibit a combination of enhanced potency and reduced toxicity over the naturally occurring and presently known cyclosporins. ISATX247 isomers and alkylated, arylated, and deuterated derivatives are synthesized by stereoselective pathways where the particular conditions of a reaction determine the degree of stereoselectivity. The ratio of isomers in a mixture may range from about 10 to 90 percent by weight of the (E)-isomer to about 90 to 10 percent by weight of the (Z)-isomer, based on the total weight of the mixture.
摘要翻译： 本发明涉及结构类似于环孢霉素A的环孢菌素类似物的异构体混合物。该混合物具有比单个异构体和天然存在的和其它目前已知的环孢菌素和环孢菌素衍生物更强的功效和降低的毒性。 本发明的实施方案涉及被称为ISA 247的环孢菌素A类似物及其衍生物的顺式和反式异构体。 ISA 247异构体的混合物显示了与天然存在的和目前已知的环孢菌素相比增强的效力和降低的毒性的组合。 通过立体选择性途径合成烷基化，芳基化和氘代衍生物，其中反应的特定条件决定了立体选择性的程度。 基于混合物的总重量，混合物中异构体的比例可以为（E） - 异构体的约10至90重量％至（Z） - 异构体的约90至10重量％。
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公开(公告)号：US06686454B1
公开(公告)日：2004-02-03
申请号：US09390280
申请日：1999-09-03
IPC分类号： C07K1600
CPC分类号： C07K7/64 , A61K39/00 , C07K16/14 , G01N33/9493 , Y10S435/975
摘要： This invention relates to the production of polyclonal and monoclonal antibodies to specific regions of cyclosporine (CSA) and/or CSA metabolites/derivatives. The reactivity of these polyclonal and monoclonal antibodies make them particularly useful for immunoassays for therapeutic drug monitoring (TDM). These immunoassays or TDM kits may include polyclonal or monoclonal antibodies to specific sites of CSA and/or CSA metabolites. These kits may also include various combinations of polyclonal antibodies, polyclonal and monoclonal antibodies or a panel of monoclonal antibodies. Cyclosporine or CSA metabolite conjugate immunogens are prepared for the immunization of a host animal to produce antibodies directed against specific regions of the CSA or CSA metabolite molecule. By determining the specific binding region of a particular antibody, immunoassays which are capable of distinguishing between the parent molecule, active metabolites, inactive metabolites and other structurally similar immunosuppressant compounds are developed. The use of divinyl sulfone (DVS) as the linker arm molecule for forming cyclosporine and cyclosporine metabolite protein conjugate immunogens is described.
摘要翻译： 本发明涉及针对环孢菌素（CSA）和/或CSA代谢物/衍生物的特定区域的多克隆和单克隆抗体的产生。 这些多克隆抗体和单克隆抗体的反应性使其在治疗药物监测（TDM）的免疫测定中特别有用。 这些免疫测定或TDM试剂盒可以包括针对CSA和/或CSA代谢物的特定位点的多克隆或单克隆抗体。 这些试剂盒还可以包括多克隆抗体，多克隆和单克隆抗体或一组单克隆抗体的各种组合。 制备环孢菌素或CSA代谢物缀合物免疫原用于免疫宿主动物以产生针对CSA或CSA代谢物分子的特定区域的抗体。 通过确定特定抗体的特异性结合区域，开发了能够区分亲本分子，活性代谢物，无活性代谢物和其它结构相似的免疫抑制剂化合物的免疫测定。 描述了使用二乙烯基砜（DVS）作为形成环孢菌素和环孢菌素代谢物蛋白质结合物免疫原的连接臂分子。
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17.发明授权13C glucose breath test for the diagnosis of diabetic indications and monitoring glycemic control 失效13C葡萄糖呼吸试验用于诊断糖尿病适应症并监测血糖控制公开(公告)号：US06461870B2
公开(公告)日：2002-10-08
申请号：US09910701
申请日：2001-07-20
IPC分类号： G01N3700
CPC分类号： A61B5/0813 , A61B5/0836 , A61B5/14532 , A61K51/1206 , G01N33/497 , Y10T436/104998 , Y10T436/13 , Y10T436/24 , Y10T436/25875
摘要： Use of 13C glucose in an analytical assay to monitor glucose metabolism by measurement of labeled exhaled CO2 is provided. A breath test and kit for performing the breath test are described for the diagnosis of diabetic indications and monitoring of glycemic control. The breath test utilizes the measurement of expired 13C-labeled CO2 following the ingestion of a 13C-enriched glucose source.
摘要翻译： 提供了在分析测定中使用13C葡萄糖通过测量标记的呼出二氧化碳来监测葡萄糖代谢。 描述了用于进行呼吸试验的呼吸试验和试剂盒，用于诊断糖尿病适应症和监测血糖控制。 呼吸测试在摄取富含13C的葡萄糖源后，利用过期的13C标记的CO2的测量。
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18.发明申请公开(公告)号：US20130078280A1
公开(公告)日：2013-03-28
申请号：US13684574
申请日：2012-11-26
IPC分类号： A61K38/13
CPC分类号： C07K7/645 , A61K9/0095 , A61K9/1075 , A61K9/4858 , A61K38/00 , A61K38/13 , B82Y5/00 , C07K7/64 , Y10S530/806
摘要： The invention is directed to isomeric mixtures of cyclosporine analogues that are structurally similar to cyclosporine A. The mixtures possess enhanced efficacy and reduced toxicity over the individual isomers and over naturally occurring and other presently known cyclosporines and cyclosporine derivatives. Embodiments of the present invention are directed toward cis and trans-isomers of cyclosporin A analogs referred to as ISATX247, and derivatives thereof. Mixtures of ISATX247 isomers exhibit a combination of enhanced potency and reduced toxicity over the naturally occurring and presently known cyclosporins. ISATX247 isomers and alkylated, arylated, and deuterated derivatives are synthesized by stereoselective pathways where the particular conditions of a reaction determine the degree of stereoselectivity. The ratio of isomers in a mixture may range from about 10 to 90 percent by weight of the (E)-isomer to about 90 to 10 percent by weight of the (Z)-isomer, based on the total weight of the mixture.
摘要翻译： 本发明涉及结构类似于环孢霉素A的环孢菌素类似物的异构体混合物。该混合物具有比单个异构体和天然存在的和其它目前已知的环孢菌素和环孢菌素衍生物更强的功效和降低的毒性。 本发明的实施方案涉及称为ISATX247的环孢菌素A类似物的顺式和反式异构体及其衍生物。 ISATX247异构体的混合物显示与天然存在的和目前已知的环孢菌素相比，其效力和毒性降低的组合。 ISATX247异构体和烷基化，芳基化和氘代衍生物通过立体选择性途径合成，其中反应的特定条件决定了立体选择性的程度。 基于混合物的总重量，混合物中异构体的比例可以为（E） - 异构体的约10至90重量％至（Z） - 异构体的约90至10重量％。
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公开(公告)号：US07829533B2
公开(公告)日：2010-11-09
申请号：US12197199
申请日：2008-08-22
IPC分类号： A61K38/13
CPC分类号： A61K9/1075 , A61K9/0095 , A61K9/4858 , A61K38/13 , A61K47/10
摘要： The present invention relates to formulations containing cyclosporin analogs that are structurally similar to cyclosporin A, in particular isomeric mixtures of cyclosporin analogs that are structurally similar to cyclosporin A. The formulations form stable microemulsion preconcentrates and may provide superior drug bioavailability and/or may reduce one or more adverse effects associated with the administration of cyclosporin. Also disclosed are methods for using and preparing the formulations.
摘要翻译： 本发明涉及结构上类似于环孢菌素A的环孢菌素类似物的制剂，特别是在结构上类似于环孢菌素A的环孢菌素类似物的异构体混合物中。制剂形成稳定的微乳液预浓缩物，并可提供优异的药物生物利用度和/或减少一种 或更多与施用环孢菌素相关的不良反应。 还公开了使用和制备制剂的方法。
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公开(公告)号：US20090054311A1
公开(公告)日：2009-02-26
申请号：US12197199
申请日：2008-08-22
CPC分类号： A61K9/1075 , A61K9/0095 , A61K9/4858 , A61K38/13 , A61K47/10
摘要： The present invention relates to formulations containing cyclosporin analogs that are structurally similar to cyclosporin A, in particular isomeric mixtures of cyclosporin analogs that are structurally similar to cyclosporin A. The formulations form stable microemulsion preconcentrates and may provide superior drug bioavailability and/or may reduce one or more adverse effects associated with the administration of cyclosporin. Also disclosed are methods for using and preparing the formulations.
摘要翻译： 本发明涉及结构上类似于环孢菌素A的环孢菌素类似物的制剂，特别是在结构上类似于环孢菌素A的环孢菌素类似物的异构体混合物中。制剂形成稳定的微乳液预浓缩物，并可提供优异的药物生物利用度和/或减少一种 或更多与施用环孢菌素相关的不良反应。 还公开了使用和制备制剂的方法。
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